crossing96/oncoscreening huggingface dataset:
Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.	Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.	bladder
Squamous or Glandular Differentiation Predicts Poor Prognosis in pT1 Urothelial Carcinoma.	BACKGROUND: The aim of this study was to evaluate the prognosis of patients with T1N0M0 urothelial carcinoma with squamous differentiation (UCSD) or glandular differentiation (UCGD) because it has not been determined whether these variant histologies behave more aggressively than pure urothelial carcinoma (PUC). PATIENTS AND METHODS: Ninety-nine patients diagnosed with pT1N0M0 bladder cancer and treated conservatively with transurethral resection of bladder tumor at Kanazawa University Hospital between 2007 and 2019 were included in this study. The overall survival, cancer-specific survival (CSS), and recurrence-free survival of the variant histology and PUC groups were evaluated and compared. RESULTS: The variant histology group had significantly lower overall survival (p=0.006) and CSS (p=0.0095) than the PUC group did. Variant histology was found to be an independent prognostic factor in univariate and multivariate analyses for overall survival and CSS. On the other hand, no significant difference in progression-free survival was observed between the two groups (p=0.439). However, the variant histology group had significantly lower overall survival (p=0.004) and CSS (p=0.004) after progression. CONCLUSION: The prognosis for patients with pT1 bladder cancer with UCSD or UCGD treated conservatively with transurethral resection of bladder tumor was poor. Considering the worse prognosis of these patients after stage progression, early radical cystectomy could be recommended.	bladder
[Primary melanoma of renal pelvis].	A rare case of primary renal pelvis melanoma in 47-year-old man is presented in the article. Before surgery a patient was considered to have metastatic urothelial carcinoma. A diagnosis of malignant melanoma was based on immunophenotyping and detection of intracellular melanin pigment both in pelvis tumor and lung metastasis. The primary localization in the pelvis was proven by the presence of scattered melanocytes within urothelium.The patient had no previous history ofskin or mucosa melanoma. This is the sixth case of renal pelvis melanoma published in PubMed.	bladder
[X-ray endoscopic treatment in patients with ureteral anastomotic obliteration after orthotopic neobladder formation].	"INTRODUCTION: Strictures and obliterations of ureteral anastomosis after radical cystectomy with orthotopic neobladder reconstruction occur in 8-13% of cases, mainly in the first 2 years after surgery. According to the European Association of Urology guidelines, open reconstruction is considered the ""gold standard"" for the treatment of those patients. At the same time, according to various publications, X-ray endoscopic treatment of ureteral anastomotic strictures can be performed, especially in patients who have undergone orthotopic neobladder reconstruction. MATERIALS AND METHODS: Three clinical cases of endoscopic treatment of ureteral anastomotic obliteration after orthotopic neobladder formation are presented. In all patients, nephrostomy tube was initially put due to acute pyelonephritis. Obliteration of the ureteral anastomosis was diagnosed by contrast-enhanced multispiral computed tomography and antegrade pyelography. The length of obliteration in all patients did not exceed 1.0 cm. The recurrence of the bladder cancer was excluded. After percutaneous opacification of the pelvicalyceal system and advancement of two guidewires (""working"" and ""safety"") to the level of ureteral obliteration, a catheter with a built-in fiber optic light source was put in antegrade fashion along the ""working"" guidewire to the area of obliteration. During transurethral inspection of the reservoir, the distal end of the light source was visualized and the reservoir wall was cut ""to the light"" using electrosurgery (n=2) and a thulium fiber laser (one case). For adequate kidney drainage, two internal stents of 6 Fr were put for a period of 6 months in two patients and for 2 months in another case. RESULTS: All patients had an adequate diameter of the ureteral anastomosis after removal of the stents. In two cases, an adequate passage of the contrast agent through both ureters was maintained for 42 and 37 months after procedure (according to the follow-up computed tomography and excretory urography). One patient had an attack of acute pyelonephritis 2 months after the removal of internal stents due to recurrent stricture. After repeated endoscopic ureteral recanalization with putting of two internal stents for a period of 6 months, no recurrence of the stricture was observed during 28 months of follow-up. CONCLUSION: Endoscopic treatment of both primary and recurrent short ureteral anastomotic obliterations in patients with orthotopic neobladder allows for adequate ureteral patency, provided that two internal stents are left in place for 6 months."	bladder
Prevalence and risk estimation of cancer-predisposing genes for upper urinary tract urothelial carcinoma in Japanese.	Upper urinary tract urothelial carcinoma is a rare cancer that has been associated with mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2. In addition, patients with pathogenic variants of cancer-predisposing genes such as BRCA1 and BRCA2 have been reported. However, how cancer-predisposing genes affect the risk of upper urinary tract urothelial carcinoma in the Japanese population remains unclear. Thus, we performed a case-control sequencing study of 27 cancer-predisposing genes in 208 upper urinary tract urothelial carcinoma patients and 37 727 controls. Only MSH6 and MSH2 were observed with a value of P < 0.05. However, there was no difference in the prevalence of pathogenic variants of BRCA1/2, which does not support the use of a poly adenosine diphosphate-ribose polymerase inhibitor in patients with upper urinary tract urothelial carcinoma. Only mismatch repair genes were associated with patients with upper urinary tract urothelial carcinoma, but the prevalence of pathogenic variants in mismatch repair genes was lower than that reported in previous studies from other populations.	bladder
AhRR methylation contributes to disease progression in urothelial bladder cancer.	BACKGROUND: Bladder Cancer (BCa) is the tenth most incident malignancy worldwide. BCa is mostly attributed to environmental exposure and lifestyle, particularly tobacco smoking. The Aryl Hydrocarbon Receptor Repressor (AhRR) participates in the induction of many enzymes involved in metabolizing carcinogens, including tobacco smoke components. Additionally, studies have shown that smoking demethylates the (AhRR) gene in blood, suggesting AhRR demethylation as a specific serum smoking biomarker. OBJECTIVE: This study aimed to validate AhRR demethylation as a smoking biomarker in the target tissue and investigate its contribution to bladder carcinogenesis. METHODS: AhRR percent methylation was tested for its association with patient smoking status and oncogenic outcome indicators, particularly p53, RB1, and FGFR3 activating mutations, muscle-invasiveness, and tumor grade, in 180 BCa tissue-based DNA. RESULTS: Results showed significantly higher AhRR percent methylation in muscle-invasive compared to non-muscle invasive tumors (42.86% vs. 33.98%; p= 0.011), while lower AhRR methylation was significantly associated with FGFR3 Codon 248 mutant genotype compared to wild-type (28.11% ± 9.44 vs. 37.87% ± 22.53; p= 0.036). All other tested associations were non-statistically significant. CONCLUSIONS: Although AhRR methylation did not predict smoking status in BCa tumors, it may be a contributor to carcinogenesis and disease progression. Our findings constitute the basis for further research.	bladder
Chemotherapy following immune checkpoint inhibitors in patients with locally advanced or metastatic urothelial carcinoma.	BACKGROUND: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). METHODS: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities. RESULTS: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (&lt; or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients. CONCLUSION: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data.	bladder
Oncological validation and discriminative ability of pentafecta criteria after open radical cystectomy.	OBJECTIVES: To validate the pentafecta criteria (PC) proposed by the PROMETRICS group for outcome reporting after radical cystectomy in an open radical cystectomy (ORC) cohort with long-term follow-up and to assess the discriminative ability of PC attainment for oncological endpoints. PATIENTS AND METHODS: Between January 2009 and December 2017, 420 patients underwent ORC with pelvic lymph node dissection and urinary diversion for non-metastatic bladder cancer. The PC were defined as reported by the PROMETRICS group. The primary endpoint was PC attainment, and oncological outcomes comprised further endpoints. We used uni- and multivariable logistic regression analysis to assess predictors of PC attainment. The discriminative ability of PC for overall mortality (OM), cancer-specific mortality (CSM) and other-cause mortality (OCM) was compared using Kaplan-Meier curves and cumulative incidence functions. After stratification by the number of PC attained, the association between PC attainment and the survival endpoints was tested on multivariable Cox regression and competing-risks models. RESULTS: A total of 108 patients (26%) fulfilled all PC, while 195 (46%), 77 (18%), 35 (8.3%) and five (1.2%) attained 4/5, 3/5, 2/5 and ≤1/5 PC, respectively. Increasing age-adjusted Charlson comorbidity index (odds ratio [OR] 0.80, P = 0.015) and incontinent diversion (OR 0.38, P = 0.005) were independent predictors of PC non-attainment. The median follow-up was 73 months. PC attainment (≥4/5 vs 3/5 vs ≤2/5 PC attained) was used to stratify patients into groups at significantly different risk of death (P < 0.001). A decreasing number of PC attained (<4/5) was associated with unfavourable survival estimates for both OM and CSM (all P ≤ 0.005) but not for OCM (all P ≥ 0.2). CONCLUSIONS: The PC proposed by the PROMETRICS group represent accurate quality indicators for oncological outcome reporting after ORC for non-metastatic bladder cancer and have a distinct discriminative ability to predict long-term OM and CSM.	bladder
Clinical and Patient-Reported Outcomes of Advanced Urothelial Carcinoma Following Discontinuation of PD-1/L1 Inhibitor Therapy.	INTRODUCTION: The patterns of care and attrition of locally advanced or metastatic urothelial carcinoma (la/mUC) patients eligible for systemic therapy following PD-1/L1 inhibitors are unclear. The objective of this study was to evaluate the clinical characteristics and treatment patterns among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1 inhibitor therapy. METHODS: An ambispective, multisite, chart review study was conducted in the United States, including patients with la/mUC. Eligible patients had initiated and subsequently discontinued PD-1/L1 therapy in the 1L or 2L setting for la/mUC between May 2016 and July 2018; with follow-up through October 2019. Patient characteristics, treatments, and overall survival (OS) were described. Patients had the option to complete a 1-time patient reported outcomes (PRO) survey. RESULTS: Among 300 patients included in the chart review, 198 (66%) received 1L PD-1/L1 inhibitor and 102 (34%) received 2L PD-1/L1 inhibitor. Following discontinuation of PD-1/L1 inhibitor therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The median OS post-1L PD-1/L1 inhibitor was 9.4 (95% CI 8.6-NA) and 2.5 months (95% CI 2.24-3.50) for those who received and did not receive subsequent therapy, respectively. Following 2L PD-1/L1 inhibitor discontinuation, the median OS was 5.7 (95% CI 5.1-7.8) and 3.98 (95% CI 3.29-4.87) months for those who received and did not receive subsequent therapy, respectively. Among those with PRO data, 64% reported experiencing cancer-related pain and 29.6% received an opioid. Only 12.7% reported having a caregiver, requiring approximately 13 h/d of service. CONCLUSION: The symptom and caregiver burden are high among real-world patients with la/mUC who discontinued 1L or 2L PD-1/L1 inhibitors and outcomes are dismal, with a minority receiving subsequent therapy. Patterns of care in the setting of 1L maintenance avelumab and novel agents require further investigation.	bladder
Automated Cell Phenotyping for Imaging Mass Cytometry.	Imaging mass cytometry (IMC) is a new advancement in tissue imaging that is quickly gaining wider usage since its recent launch. It improves upon current tissue imaging methods by allowing for a significantly higher number of proteins to be imaged at once on a single tissue slide. For most analyses of IMC data, determining the phenotype of each cell is a crucial step. Current methods of phenotyping require sufficient biological knowledge regarding the protein expression profile of the various cell types. Here, we develop a deep convolutional autoencoder-classifier to automate the cell phenotyping process into four basic cell types. Biopsy tissue from bladder cancer patients is used to evaluate the efficacy of the classification. The model is evaluated and validated through feature importance, confirming that the significant features are biologically relevant. Our results demonstrate the potential of deep learning to automate the task of cell phenotyping for high-dimensional IMC data.	bladder
Artificial intelligence-driven consensus gene signatures for improving bladder cancer clinical outcomes identified by multi-center integration analysis.	To accurately predict the prognosis and further improve the clinical outcomes of bladder cancer (BLCA), we leveraged large-scale data to develop and validate a robust signature consisting of small gene sets. Ten machine-learning algorithms were enrolled and subsequently transformed into 76 combinations, which were further performed on eight independent cohorts (n = 1218). We ultimately determined a consensus artificial intelligence-derived gene signature (AIGS) with the best performance among 76 model types. In this model, patients with high AIGS showed a higher risk of mortality, recurrence, and disease progression. AIGS is not only independent of traditional clinical traits [(e.g., American Joint Committee on Cancer (AJCC) stage)] and molecular features (e.g., TP53 mutation) but also demonstrated superior performance to these variables. Comparisons with 58 published signatures also indicated that AIGS possessed the best performance. Additionally, the combination of AIGS and AJCC stage could achieve better performance. Patients with low AIGS scores were sensitive to immunotherapy, whereas patients with high AIGS scores might benefit from seven potential therapeutics: BRD-K45681478, 1S,3R-RSL-3, RITA, U-0126, temsirolimus, MRS-1220, and LY2784544. Additionally, some mutations (TP53 and RB1), copy number variations (7p11.2), and a methylation-driven target were characterized by AIGS-related multi-omics alterations. Overall, AIGS provides an attractive platform to optimize decision-making and surveillance protocol for individual BLCA patients.	bladder
Comprehensive Landscape of Cyclin Pathway Gene Alterations and Co-occurrence with FGF/FGFR Aberrations Across Urinary Tract Tumors.	BACKGROUND: Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies. PATIENTS AND METHODS: Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated. RESULTS: Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (n = 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1). CONCLUSIONS: Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities.	bladder
Impact of Effective Intravesical Therapies on Quality of Life in Patients with Non-Muscle Invasive Bladder Cancer: A Systematic Review.	BACKGROUND: Conventional and newly emerged intravesical modalities have demonstrated prophylactic effectiveness that may improve quality of life (QoL) in non-muscle invasive bladder cancer. The purpose of this study is to analyze existing QoL evidence in patients receiving any form of intravesical therapy. METHODS: A PubMed search without time restriction was conducted to identify all relevant studies in accordance with the PICOT question. Additionally, a search was also performed in the Cochrane library database, Internet, and citation. The CONSORT 2010 checklist and STROBE statement checklist were used to evaluate the risk of bias of the included studies. RESULTS: A total of 24 eligible articles were included, which consisted of 11 interventional and 13 observational studies. Intravesical therapy with Bacillus Calmette-Guérin (BCG) or certain chemotherapeutic agents worsens symptom burdens and functional performance during the initial induction phase while continuous improved is observed throughout the maintenance treatment and beyond. Hyperthermia has shown a positive trend in enhancing QoL of patients receiving intravesical chemotherapy, which requires more investigations. However, QoL data were unavailable for other forms of immunotherapy, immune checkpoint inhibitors, electromotive drug administration, and photodynamic therapy. CONCLUSIONS: Limited studies suggested the long-term positive impact of intravesical BCG immunotherapy and chemotherapy. However, existing evidence was lacking to clarify the impact of many emerging intravesical therapies that have suggested to be effective and safe, which demands treatment-specific QoL studies.	bladder
MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3.	The transcription factor MYB proto-oncogene like 2 (MYBL2) is critical in regulating gene expression and tumorigenesis. However, the biological function of MYBL2 in bladder cancer (BLCA) remains to be elucidated. Here, we first revealed that MYBL2 was elevated in BLCA tissues and significantly correlated with clinicopathological parameters and cancer-specific survival in BLCA patients. Phenotypic assays showed that MYBL2 deficiency suppressed the proliferation and migration of BLCA cells in vitro and in vivo, whereas MYBL2 overexpression contributed to the opposite phenotype. Mechanistically, MYBL2 could bind to the promoter of its downstream target gene cell division cycle-associated protein 3 (CDCA3) and transactivate it, which in turn promoted the malignant phenotype of BLCA cells. Further investigations revealed that MYBL2 interacted with forkhead box M1 (FOXM1) to co-regulate the transcription of CDCA3. In addition, MYBL2/FOXM1 and CDCA3 might activate Wnt/β-catenin signaling, thereby promoting the malignant phenotype of BLCA cells. In conclusion, the current study identifies MYBL2 as an oncogene in BLCA. MYBL2 can accelerate the proliferation and metastasis of BLCA through the transactivation of CDCA3.	bladder